The references cited herein are not admitted to be prior art to the claimed invention.
The pulsatile release of growth hormone from the pituitary somatotrops is regulated by two hypothalamic neuropeptides: growth hormone-releasing hormone and somatostatin. Growth hormone-releasing hormone stimulates release of growth hormone, whereas, somatostatin inhibits secretion of growth hormone. (Frohman et al., Endocronol. Rev. 1986, 7, 223-253, and Strobl et al., Pharmacol. Rev. 1994, 46, 1-34.)
Release of growth hormone from the pituitary somatotrops can also be controlled by growth hormone-releasing peptides. A hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-amide (GHRP-6), was found to release growth hormone from somatotrops in a dose-dependent manner in several species including man. (Bowers et al., Endocrinology 1984, 114, 1537-1545.) Subsequent chemical studies on GHRP-6 led to the identification of other potent growth-hormone secretagogues such as GHRP-1, GHRP-2 and hexarelin (Cheng et al., Endocrinology 1989, 124, 2791-2798, Bowers, C. Y. Novel GH-Releasing Peptides. In: Molecular and Clinical Advances in Pituitary Disorders. Ed: Melmed, S.; Endocrine Research and Education, Inc., Los Angeles, Calif., USA 1993, 153-157, and Deghenghi et al., Life Sci. 1994, 54, 1321-1328):
GHRP-1Ala-His-D-(2′)-Nal-Ala-Trp-D-Phe-Lys-NH2GHRP-2D-Ala-D-(2′)-Nal-Ala-Trp-D-Nal-Lys-NH2HexarelinHis-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH2.
GHRP-1, GHRP-2, GHRP-6, and hexarelin are synthetic growth-hormone secretagogues. Growth-hormone secretagogues stimulate secretion of growth hormone by a mechanism different from that of growth hormone-releasing hormone, but like growth hormone-releasing hormone, they antagonize release of somatostatin from the pituitary and hypothalamus. (Bowers et al., Endocrinology 1984, 114, 1537-1545, Cheng et al., Endocrinology 1989, 124, 2791-2798, Bowers, C. Y. Novel GH-Releasing Peptides. In: Molecular and Clinical Advances in Pituitary Disorders. Ed: Melmed, S.; Endocrine Research and Education, Inc., Los Angeles, Calif., USA 1993, 153-157, and Deghenghi et al., Life Sci. 1994, 54, 1321-1328.)
The low oral bioavailability (<1%) of the peptidyl growth-hormone secretagogues stimulated search for non-peptide compounds mimicking action of GHRP-6 in the pituitary. Several benzolactams and spiroindanes have been reported to stimulate growth-hormone release in various animal species and in man. (Smith et al., Science 1993, 260, 1640-1643, Patchett et al., Proc. Natl. Acad. Sci. USA. 1995, 92, 7001-7005, and Chen et al., Bioorg. Med. Chem. Lett. 1996, 6, 2163-2169.) A specific example of a small spiroindane is MK-0677 (Patchett et al. Proc. Natl. Acad. Sci. USA. 1995, 92, 7001-7005): 
The actions of the above-mentioned growth-hormone secretagogues (both peptide and non-peptide) appear to be mediated by a specific growth-hormone secretagogue receptor (GHS receptor). (Howard et al., Science 1996, 273, 974-977, and Pong et al., Molecular Endocrinology 1996, 10, 57-61.) This receptor is present in the pituitary and hypothalamus of various mammalian species (GHSR1a) and is distinct from the growth hormone-releasing hormone receptor. The GHS receptor was also detected in the other areas of the central nervous system and in peripheral tissues, for instance adrenal and thyroid glands, heart, lung, kidney and skeletal muscles. (Chen et al., Bioorg. Med. Chem. Lett. 1996, 6, 2163-2169, Howard et al., Science 1996, 273, 974-977, Pong et al., Molecular Endocrinology 1996, 10, 57-61, Guan et al., Mol. Brain Res. 1997, 48, 23-29, and McKee et al., Genomics 1997, 46, 426-434.) A truncated version of GHSR1a has been reported. (Howard et al., Science 1996, 273, 974-977.)
The GHS receptor is a G-protein coupled-receptor. Effects of GHS receptor activation includes depolarization and inhibition of potassium channels, an increase in intercellular concentrations of inositol triphosphate (IP3), and a transient increase in the concentrations of intracellular calcium. (Pong et al., Molecular Endocrinology 1996, 10, 57-61, Guan et al., Mol. Brain Res. 1997, 48, 23-29, and McKee et al., Genomics 1997, 46, 426-434.)